1. Field of the Invention
The present invention relates to novel hydroxyphenylundecane derivatives, a method for the preparation of said compounds and their use as pharmaceuticals, i.e. for the treatment of Alzheimer's Disease, Parkinson's Disease, Huntington's Diseases, stroke, psychosis and/or depressions.
2. Description of the Art
Differential expression and localization of c-Jun N-terminal kinases (JNKs) in the human brain reflects transduction of a variety of extracellular stimuli to selective cellular responses. Of the 3 JNKs, JNK1 and JNK2 are widely distributed in tissues and JNK3 is predominantly restricted to brain where it is expressed in neurons. The c-Jun N-terminal Kinase (JNK) pathway leading to c-Jun phosphorylation plays a causal role in apoptosis of isolated primary embryonic neurons and of multiple neuronal cell lines following a wide variety of stimuli. Activation of this pathway is suggested to contribute to the neuronal atrophy and death that is associated with neurodegenerative pathological conditions including Alzheimer's Disease, Parkinson's Disease, Huntington's Diseases and stroke (Kumagae et al., Mol. Brain Res. (1999), 67(1), 10–7). Inhibitors of JNK3 therefore should stop apoptosis and be useful for the treatment and/or prevention of the above mentioned diseases.
Protein phosphatase-1 (PP1) is a serine/threonine phosphatase that plays an important role in a variety of cellular processes, including muscle contraction, cell-cycle progression, and neurotransmission (Hsieh-Wilson et al., Biochemistry 1999, 38, 4365–4373). The localization and substrate specifity of PP1 are determined by a class of proteins known as targeting subunits. Targeting subunits restrict the otherwise broad specifity of the catalytic subunit (PP1c) by directing the enzyme to discrete subcellular compartments and, in some cases, by modulating its activity toward particular substrates. Studies support the notion that spinophilin, a protein highly enriched in dendritic spines, functions as a neuronal targeting subunit of PP1. Spinophilin plays an important role in regulating the phosphorylation states of glutamate receptors in dendritic spines e.g. the glutamat receptor AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) by anchoring PP1 in the proximity of these receptors (Jiang Feng et al., Proc. Natl. Acad. Sci. USA 2000, 97, 9287–9292). In the absence of spinophilin, AMPA receptors are no longer subjected to down-regulation by PP1, which results in more persistent AMPA receptor currents. Dysregulation of glutamate receptor currents leads to specific changes in neuronal circuits, which may lead e.g. to long-term depression. Molecules that interfere with the spinophyllin-PP1 interaction are therefore useful for the treatment or prevention of psychosis or depressions.
Dimerized hydroxyphenylundecane of the formula
wherein    when “a” represents a single bond, R is —OH or —OC(O)CH3, and    when “a” represents a double bond, R is absent,have been described as HIV integrase inhibitors in UK patent application GB 2327674.